Subjects with impaired fasting glucose have increased risk of progression to T2DM. The metabolic defects responsible for the increase in FPG within the nondiabetic range have been poorly studied. A clearer understanding of the mechanisms of these defects will help to develop improved strategies to treat and prevent T2DM. We previously have shown that basal glucose clearance is decreased in IFG subjects. Since basal tissue glucose clearance takes place via glucose-mediated glucose uptake (GMGU) mechanisms, we hypothesize that impaired GMGU is the primary defect responsible for the rise in the FPG concentration in the non-diabetic range and development of IFG. In this grant proposal we will: (i) quantitate whole body GMGU with the stepped hyperglycemic clamp and somatostatin infusion, and insulin-mediated glucose uptake (IMGU) with the stepped euglycemic insulin clamp, (ii) the protein content of insulin dependent (GLUT4/GLUT12) and glucose-mediated glucose transporters (GLUT1/GLUT3/GLUT11) and gene expression in skeletal muscle in subjects with IFG, IGT and NGT; (iii) the level of transcription factors and mRNA binding proteins and their binding to GLUT1 gene promoter and GLUT1 mRNA and their relationship to GLUT1 level, and (iv) quantitate splanchnic glucose uptake (SGU) during basal state and following glucose ingestion to examine the contribution of decreased SGU to the decreased GMGU and excessive early rise in plasma glucose concentration in IFG subjects. We believe that the results of these studies will help define the molecular/biochemical/physiologic defects responsible for the development of IFG and help to elucidate effective strategies to correct these defects and revert IFG to NGT. PUBLIC HEALTH RELEVANCE: Subjects with impaired fasting glucose (IFG) have increased future risk for type 2 diabetes (T2DM). In this grant proposal, we will study the molecular, metabolic and physiologic defects responsible for the increase in the fasting plasma glucose concentration during the non-diabetic range and development of IFG. Thus, the results of the present studies will improve the understanding of the regulation of glucose homeostasis and will help identify novel targets for intervention to prevent the progression of IFG to T2DM and revert IFG to NGT.